Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown cause that affects primary joints. Human leukocyte antigen-antigen D related (HLA-DR) molecules play a central role in autoimmune diseases, as first reported by McDevitt in 1974, (1) HLA-DR molecules are highly expressed in synovial tissue (ST), the target of the immune response in chronic inflammatory forms of arthritis, including rheumatoid arthritis (RA) and Lyme arthritis (LA) (2, 3). The greatest known genetic risk factors for these diseases are certain HLA-DR alleles (4). HLA-DR molecules present foreign or self-peptides to CD4+ T cells, leading to their activation (5). After activation, T cells can supply the necessary help to B cells to produce sustained, high-titer antibodies against the same antigen. In RA, 10 HLA-DR alleles, including the HLA-DRB1*0101 and 0401 alleles (6, 7) convey the greatest risk. These alleles code for a similar sequence of amino acids, called the RA shared epitope, which line the P4 pocket of the HLA-DR molecule. Anti-citrullinated protein antibodies (ACPA), which are specific for RA, are significantly more frequent in patients who have the shared epitope (8-13).
In both RA and LA, synovial tissue shows marked synovial hypertrophy, vascular proliferation, mononuclear cell infiltration, and intense expression of HLA-DR molecules on synoviocytes and infiltrating cells (2, 3). The tissue is bathed in synovial fluid (SF), which contains a rich mixture of inflammatory cells, including large numbers of dendritic cells and macrophages; the latter also have increased expression of HLA-DR molecules (28, 29). However, the repertoire of specific self-peptides presented by HLA-DR molecules in synovial tissues in RA is unknown. Accordingly there is an unmet need of identifying autoantigens presented by HLA-DR and pathogenic T-cell epitopes in synovial tissues, synovial fluid as well as peripheral blood mononuclear cells of RA patients.